The control of both hepatic gluconeogenesis and hepatic mixed function oxidation (drug metabolism) are interrelated and under hormonal control. This interrelationship and its control are greatly affected by diabetes. The overall objective of the proposed research is to determine the nature of these integrated control mechanisms. The specific objectives include the identification of a glucagon and diabetes-induced cytosol-located inhibitor of hepatic mixed function oxidation and determination of the mechanism of influence of the gluconeogenic process (as influenced by substrate-type, glucagon and diabetes) on hepatic mixed function oxidation via such factors as competition for NADPH producing substrates, alteration of hepatic redox state and changes in the concentration of known metabolic-intermediate effectors of hepatic mixed function oxidation. Isolated perfused normal and diabetic rat and guinea pig liver will be the focus of the integrated research procedures used to study these control phenomena. Other procedures to be used include in vitro assays with isolated microsomes and various chromatographic techniques.